Familial hypercholesterolemia is an inherited disorder that results in high serum cholesterol levels attributable to an elevated level of cholesterol-carrying low-density lipoprotein (LDL). This condition leads to deposition of LDL-derived cholesterol in several tissues, especially tendons and arteries, which results in a high incidence of heart attack and ultimately death. Existing drug and plasma exchange therapies have significant drawbacks. We propose to explore the treatment of hypercholesterolemia with a membrane-immobilized enzyme system that removes cholesterol-carrying protein from the blood and returns the cleansed plasma to the patient. Plasma will be contacted with an LDL-degrading enzyme in order to render the LDL particles capable of being separated from the plasma, e.g., in a standard blood or membrane filter. In Phase I, a knowledge base will be established that will permit the rational design of a plasma separator/bioreactor module for the extracorporeal removal of LDL. In Phase II, we will construct and test prototype LDL-removal modules both in vitro and in animals. The purpose of this project is thus to establish the technical basis for enzymatic LDL removal, to create a new business opportunity in extracorporeal blood processing, and to address the medical needs of afflicted individuals who are poorly served by existing hypercholesterolemia therapies.